Metabolic diseases include obesity type 2 diabetes mellitus (insulin resistance) and non-alcoholic fatty liver disease (NAFLD). These disorders are associated with increased risk for cardiovascular diseases such as atherosclerosis and non-alcoholic steatohepatitis (NASH), and cancer. There is a marked increase in cancer risk of over 35% depending on the cancer type, associated with obesity, and insulin resistance. NAFLD and NASH are associated with markedly increased risk for liver cancer. A chronic imbalance between energy intake and energy expenditure causes obesity for which there is no safe and effective drug therapy. Bile acids including chenodeoxycholic acid (CDCA), deoxycholic acid (DCA), and lithocholic acid (LCA) are endogenous activators of the farnesoid X receptor (FXR). In addition, the conjugated bile acid tauro-beta-muricholic acid (T-beta-MCA), that is modulated by the gut microbiota was found to be a natural FXR antagonist in mice, and increased intestinal T-beta-MCA levels ameliorate HFD-induced obesity, glucose intolerance and NAFLD via inhibition of intestinal FXR signaling However, the molecular mechanism by which intestinal FXR restores HFD-disrupted glucose homeostasis is poorly understood and the subject of the current study. While T-beta-MCA is a natural FXR antagonist produced in liver, it is rapidly hydrolyzed into beta-MCA by bile salt hydrolase (BSH) in the gut, resulting in levels that are too low in the intestine to inhibit FXR signaling. Therefore, inhibition of bacterial BSH could block intestinal FXR signaling by increasing intestinal T-beta-MCA. Caffeic acid phenethyl ester (CAPE), an over-the-counter dietary supplement and an inhibitor of bacterial BSH, increased levels of intestinal T-beta-MCA, which selectively suppresses intestinal FXR signaling. Intestinal FXR inhibition decreased ceramides by suppressing expression of the novel FXR target genes Smpd3 and Sptlc2 in intestinal ileum epithelial cells. The lower serum ceramides mediated decreased hepatic mitochondrial acetyl-CoA levels and pyruvate carboxylase activities, and attenuated hepatic gluconeogenesis, independent of body weight change and hepatic insulin signaling in vivo; this was reversed by treatment of mice with ceramides or the FXR agonist GW4064. Ceramides substantially attenuated mitochondrial citrate synthase activities primarily through induction of endoplasmic reticulum stress, which triggers increased hepatic mitochondrial acetyl-CoA levels and pyruvate carboxylase activities. These results reveal a mechanism by which the dietary supplement caffeic acid phenethyl ester and intestinal FXR regulates hepatic gluconeogenesis, and suggest that inhibiting intestinal FXR is a strategy for treating hyperglycemia. Another study found that FXR influences chemically-induced liver toxicity. Hepatotoxicity is of major concern for humans exposed to industrial chemicals and drugs. Disruption of farnesoid X receptor (FXR), a master regulator of bile acid (BA) metabolism, enhanced the sensitivity to liver injury in mice after toxicant exposure, but the precise mechanism remains unclear. In this study, the interconnection between BA metabolism, FXR, and chemically-induced hepatotoxicity was investigated using metabolomics, Fxr-null mice and hepatocytes, and adenovirus. A single low-dose intraperitoneal injection of carbon tetrachloride (CCl4), an inducer of acute hepatitis in mice, resulted in more severe hepatocyte damage and higher induction of pro-inflammatory mediators, such as chemokine (C-C motif) ligand 2 (Ccl2), in Fxr-null mice. Serum metabolomics analysis revealed marked increases in circulating taurocholate (TCA) T-beta-MCA in these mice, and forced expression of bile salt export protein (BSEP) by adenovirus in Fxr-null mice ameliorated CCl4-induced liver damage. Treatment of Fxr-null hepatocytes with TCA, but not T-beta-MCA, significantly increased c-Jun-N-terminal kinase (JNK) activation and Ccl2 mRNA levels, and up-regulation of Ccl2 mRNA was attenuated by co-treatment with a JNK inhibitor SP600125, indicating that TCA directly amplifies hepatocyte inflammatory signaling mainly mediated by JNK under FXR-deficiency. Additionally, pre-treatment with SP600125 or restoration of FXR expression in liver by use of recombinant adenovirus, attenuated CCl4-induced liver injury. Collectively, these results suggest that the TCA-JNK axis is likely associated with increased susceptibility to CCl4-induced acute liver injury in Fxr-null mice, and provide clues to the mechanism by which FXR and its downstream gene targets, such as BSEP, protects against chemically-induced hepatotoxicity. The enzymology by which MCA is synthesized was not known. Mice and rats can hydroxylate chenodeoxycholic acid (CDCA) at the 6beta-position to form alpha- MCA, and ursodeoxycholic acid (UDCA) to form beta-MCA). However, MCA is not formed in humans to any appreciable degree and the mechanism for this species difference is not known. Comparison of several Cyp-null mouse lines revealed that alpha-MCA and beta-MCA were not detected in the liver samples from Cyp2c-cluster null (Cyp2c-null) mice. Global bile acids analysis further revealed the absence of MCA and their conjugated-derivatives, and high concentration of CDCA, UDCA in Cyp2c-null mouse cecum and feces. Analysis of recombinant CYPs revealed that alpha-MCA and beta-MCA were produced by oxidation of CDCA and UDCA by Cyp2c70. CYP2C9-humanized mice have similar bile acid metabolites as the Cyp2c-null mice, indicating that human CYP2C9 does not oxidize CDCA and UDCA thus explaining the species differences in production of MCA. Since humans do not produce MCA, they lack T-beta-MCA, the natural FXR antagonists in mouse, that modulates obesity, insulin resistance and NAFLD as described above